Gene therapy for lysosomal storage disorders

Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Box 100296, Gainesville, FL 32610-0296, USA 

ADENO-ASSOCIATED VIRAL VECTORS FOR GENE THERAPY 

There are over 40 lysosomal storage disorders (LSDs) characterized by the specific enzyme deficiency and accumulated substrate. Pathologies associated with LSDs are multisystemic and variable including CNS, skeletal, cardiovascular, renal, and ocular system involvement. The aggregate incidence is estimated to approach 1 in 7000 live births (Ellinwood et al., 2004). Inheritance for LSDs is primarily autosomal recessive with the exception of two X-linked diseases (Fabry and mucopolysaccharidosis (MPS) II). Treatment for LSDs relies on providing functional enzyme to the lysosomes of affected cells and has traditionally been confined to bone marrow transplantation, and enzyme replacement therapy (ERT). 

The most commonly used therapy to treat LSDs is heterologous bone marrow transplantation (BMT). This treatment provides both normal bone marrow and bone marrow-derived cells, which release enzyme continuously. Unfortunately, BMT is associated with several problems and risks including the availability of a suitable donor, poor response to therapy, and sustained immune suppression. BMT therapies for MPS I, MPS II, MPS III, metachromatic leukodystrophy, and non-neuronopathic forms of Gaucher disease have demonstrated promising results. In most successful cases, the pathology is reversed in the visceral organs with variable or unclear success in the CNS (Laine et al., 2004). 

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Beck M (2007) New therapeutic options for lysosomal storage disorders enzyme replacement, small molecules and gene therapy. Hum Genet 121 1-22... 

Gene therapy progress for lysosomal storage disorders as of 2004... 

Lysosomal storage disorders (LSDs) constitute an important group of conditions in which the potential of gene manipulation as therapy can be assessed. They are monogenic defects, often with severe manifestations for which there are limited treatment options. Overexpression of tlie lysosomal hydrolase by gene-conected cells results in secretion of some of the enzyme and its uptake by uncorrected bystander cells (metabolic cooperativity). Gene therapy shategies, enzyme therapy and bone maiiow transplantation have all been described. 

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